The role of raptor in the mechanical load‐induced regulation of mTOR signaling, protein synthesis, and skeletal muscle hypertrophy

You, Jae‐Sung; McNally, Rachel M.; Jacobs, Brittany L.; Privett, Rachel E.; Gundermann, David M.; Lin, Kuan‐Hung; Steinert, Nate D.; Goodman, Craig A.; Hornberger, Troy A.

doi:10.1096/fj.201801653rr

Cited by 123 publications

(174 citation statements)

References 58 publications

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“…To examine whether iRAmKO mice display similar alterations, we examined cross‐sections from TA muscles 21 days, 3 months, and 5 months after TAM injection. Twenty‐one day iRAmKOs depicted no changes (Supporting Information, Figure A ), consistent with a previous report . After 3 months, despite some fibres from iRAmKO mice appearing more roundish ( Figure A) and an increased variation in Type 2A fibre size distribution and variance coefficient (Supporting Information, Figure S2B and S2D), overall fibre size, fibre size distribution, and variance coefficient were unchanged compared with control littermates (Supporting Information, Figure S2C, S2E , S2F, and S2G ).…”

Section: Resultssupporting

confidence: 90%

“…This lack of an increase of non‐polysome ribosomal subunits in iRAmKO muscle is possibly because of the decrease in ribosomal proteins. Hence, removal of raptor does lead to a reduction in global translation, consistent with the results of others . Despite this reduction, iRAmKO muscles do not display any atrophy up to 5 month post‐raptor depletion ( Figures D and ).…”

Section: Resultssupporting

confidence: 89%

“…Using experimental paradigms of hypertrophy, it has been clearly demonstrated that mTORC1 inhibition blunts hypertrophy . However, definitive evidence for a role of mTORC1 in the maintenance of adult muscle mass is largely missing.…”

Section: Discussionmentioning

confidence: 99%

“…Our results are thus different from those obtained when the increase in load causes muscle hypertrophy. In all those paradigms, mTORC1 signalling strongly contributes to hypertrophy …”

Section: Discussionmentioning

confidence: 99%

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mTORC1 signalling is not essential for the maintenance of muscle mass and function in adult sedentary mice

Ham

Chojnowska

Tintignac

et al. 2019

J cachexia sarcopenia muscle

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Background The balance between protein synthesis and degradation (proteostasis) is a determining factor for muscle size and function. Signalling via the mammalian target of rapamycin complex 1 (mTORC1) regulates proteostasis in skeletal muscle by affecting protein synthesis and autophagosomal protein degradation. Indeed, genetic inactivation of mTORC1 in developing and growing muscle causes atrophy resulting in a lethal myopathy. However, systemic dampening of mTORC1 signalling by its allosteric inhibitor rapamycin is beneficial at the organismal level and increases lifespan. Whether the beneficial effect of rapamycin comes at the expense of muscle mass and function is yet to be established. Methods We conditionally ablated the gene coding for the mTORC1‐essential component raptor in muscle fibres of adult mice [inducible raptor muscle‐specific knockout (iRAmKO)]. We performed detailed phenotypic and biochemical analyses of iRAmKO mice and compared them with muscle‐specific raptor knockout (RAmKO) mice, which lack raptor in developing muscle fibres. We also used polysome profiling and proteomics to assess protein translation and associated signalling in skeletal muscle of iRAmKO mice. Results Analysis at different time points reveal that, as in RAmKO mice, the proportion of oxidative fibres decreases, but slow‐type fibres increase in iRAmKO mice. Nevertheless, no significant decrease in body and muscle mass or muscle fibre area was detected up to 5 months post‐raptor depletion. Similarly, ex vivo muscle force was not significantly reduced in iRAmKO mice. Despite stable muscle size and function, inducible raptor depletion significantly reduced the expression of key components of the translation machinery and overall translation rates. Conclusions Raptor depletion and hence complete inhibition of mTORC1 signalling in fully grown muscle leads to metabolic and morphological changes without inducing muscle atrophy even after 5 months. Together, our data indicate that maintenance of muscle size does not require mTORC1 signalling, suggesting that rapamycin treatment is unlikely to negatively affect muscle mass and function.

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Section: Resultssupporting

confidence: 90%

Section: Resultssupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

“…Our results are thus different from those obtained when the increase in load causes muscle hypertrophy. In all those paradigms, mTORC1 signalling strongly contributes to hypertrophy …”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

mTORC1 signalling is not essential for the maintenance of muscle mass and function in adult sedentary mice

Ham

Chojnowska

Tintignac

et al. 2019

J cachexia sarcopenia muscle

View full text Add to dashboard Cite

show abstract

“…mouse was also reported by another group which generated an inducible, muscle‐specific Raptor k.o. mouse …”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle mTORC1 regulates neuromuscular junction stability

Baraldo

Geremia

Pirazzini

et al. 2019

J cachexia sarcopenia muscle

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Background Skeletal muscle is a plastic tissue that can adapt to different stimuli. It is well established that Mammalian Target of Rapamycin Complex 1 (mTORC1) signalling is a key modulator in mediating increases in skeletal muscle mass and function. However, the role of mTORC1 signalling in adult skeletal muscle homeostasis is still not well defined. Methods Inducible, muscle‐specific Raptor and mTOR k.o. mice were generated. Muscles at 1 and 7 months after deletion were analysed to assess muscle histology and muscle force. Results We found no change in muscle size or contractile properties 1 month after deletion. Prolonging deletion of Raptor to 7 months, however, leads to a very marked phenotype characterized by weakness, muscle regeneration, mitochondrial dysfunction, and autophagy impairment. Unexpectedly, reduced mTOR signalling in muscle fibres is accompanied by the appearance of markers of fibre denervation, like the increased expression of the neural cell adhesion molecule (NCAM). Both muscle‐specific deletion of mTOR or Raptor, or the use of rapamycin, was sufficient to induce 3–8% of NCAM‐positive fibres (P < 0.01), muscle fibrillation, and neuromuscular junction (NMJ) fragmentation in 24% of examined fibres (P < 0.001). Mechanistically, reactivation of autophagy with the small peptide Tat‐beclin1 is sufficient to prevent mitochondrial dysfunction and the appearance of NCAM‐positive fibres in Raptor k.o. muscles. Conclusions Our study shows that mTOR signalling in skeletal muscle fibres is critical for maintaining proper fibre innervation, preserving the NMJ structure in both the muscle fibre and the motor neuron. In addition, considering the beneficial effects of exercise in most pathologies affecting the NMJ, our findings suggest that part of these beneficial effects of exercise are through the well‐established activation of mTORC1 in skeletal muscle during and after exercise.

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Wireless Magnetic Robot for Precise Hierarchical Control of Tissue Deformation

Wang,

Zhao,

Han

et al. 2024

Advanced Science

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Mechanotherapy has emerged as a promising treatment for tissue injury. However, existing robots for mechanotherapy are often designed on intuition, lack remote and wireless control, and have limited motion modes. Herein, through topology optimization and hybrid fabrication, wireless magneto‐active soft robots are created that can achieve various modes of programmatic deformations under remote magnetic actuation and apply mechanical forces to tissues in a precise and predictable manner. These soft robots can quickly and wirelessly deform under magnetic actuation and are able to deliver compressing, stretching, shearing, and multimodal forces to the surrounding tissues. The design framework considers the hierarchical tissue‐robot interaction and, therefore, can design customized soft robots for different types of tissues with varied mechanical properties. It is shown that these customized robots with different programmable motions can induce precise deformations of porcine muscle, liver, and heart tissues with excellent durability. The soft robots, the underlying design principles, and the fabrication approach provide a new avenue for developing next‐generation mechanotherapy.

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The role of raptor in the mechanical load‐induced regulation of mTOR signaling, protein synthesis, and skeletal muscle hypertrophy

Cited by 123 publications

References 58 publications

mTORC1 signalling is not essential for the maintenance of muscle mass and function in adult sedentary mice

mTORC1 signalling is not essential for the maintenance of muscle mass and function in adult sedentary mice

Skeletal muscle mTORC1 regulates neuromuscular junction stability

Wireless Magnetic Robot for Precise Hierarchical Control of Tissue Deformation

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